DDDR-14. YAP/TAZ TRANSCRIPTIONAL CO-ACTIVATORS DRIVE NEURO-GLIAL STEM/PROGENITOR CELL IDENTITY IN HIGH GRADE GLIOMAS

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Abstract High-grade gliomas (HGGs), neoplasms derived from neuro-glial stem/progenitor cells, are the most common and lethal malignant primary brain tumors diagnosed in adults and children, with a median survival time of 14 months with current treatments. HGG tumorigenicity is often driven by genetic aberrations in receptor tyrosine kinases (RTKs), such as EGFR, and the Pi-3 kinase (PI3K) signaling pathway. Using Drosophila, mouse, and human HGG model systems of RTK-PI3K mutant HGGs, we identified the YAP and TAZ transcription co-activators, which regulate gene expression via TEAD co-factors, as key drivers of HGG tumorigenicity downstream of oncogenic RTK signaling. YAP and TAZ are highly expressed in RTK-mutant human HGG cells, and regulate TEAD-mediated transcription of several transcription factors, neurodevelopmental genes, and receptors, including the EGFR RTK, that together create a feedforward loop with RTKs to maintain a radial-glia-like stem/progenitor cell fate in HGG cells. Inhibition of YAP and TAZ in self-renewing stem-cell-like RTK mutant HGG cells can inhibit proliferation, block stem/progenitor cell fate, and elicit apoptosis. In particular, the benzoporphyrin derivative verteporfin, a disruptor of YAP/TAZ-TEAD mediated transcription, specifically induced apoptosis of cultured patient-derived HGG cells, suppressed expression of YAP/TAZ transcriptional targets, including RTKs, and conferred significant survival benefit in an orthotopic xenograft HGG model. Our efforts led us to initiate phase 0 and phase 1/2 clinical trials of Visudyne, an FDA-approved liposomal formulation of verteporfin, in which we have verified verteporfin uptake into tumor cells and are now testing the therapeutic efficacy of verteporfin in human patients. Finally, we have examined mechanisms of response and resistance to verteporfin, and we have evidence that stem-like HGG cells can escape the effects of YAP/TAZ inhibition by recapitulating neuro-glial developmental cell fate transitions. Together, our data indicate that targeting YAP/TAZ functionality is a promising therapeutic approach for HGG.